Expanded interest in the role of proteases and inhibitors in nervous system function and disease has developed in the past 3-5 years. This laboratory has pursued investigation into control of a balance of serine proteases and inhibitors in synapse formation, maintenance and plasticity. From preliminary work we have begun to analyze this balance in the cerebrospinal fluid (CSF) of normal subjects and predict alterations in proteases and inhibitors, now known as serpins, in Alzheimer's disease (AD). A number of proteases, capable of cleaving the beta-amyloid precursor protein, recently found to be a protease inhibitor (protease nexin II), and their respective serpins will be studied in CSF and brain tissue obtained from AD patients and disease controls. We hope to be able to estimate the amounts of active serpin available for protease inhibition in tissue as well as CSF and AD patients compared to these controls. Availability of a well-studied clinical cohort of such patients, and their rapidly frozen brain tissue from autopsy, are essential for this study.